Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) experience in patients with recurrent low grade serous ovarian carcinoma (LGSOC): sub-cohort report of phase 1 clinical trial.

Introduction: Low grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer (OC) that is challenging to treat due to its relative chemoresistance. Given that LGSOC patients often recur in the peritoneal cavity, novel intraperitoneal (IP) chemotherapy should be explored. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a method that has demonstrated peritoneal disease control in cancers with peritoneal metastases. Methods: NCT04329494 is a US multicenter phase 1 trial evaluating the safety of PIPAC in recurrent ovarian, uterine, and GI cancers with peritoneal metastases. This analysis describes the outcomes of a sub-cohort of four LGSOC patients treated with IP cisplatin 10.5 mg/m2, doxorubicin 2.1 mg/m2 PIPAC q4-6 weeks. Primary endpoints included dose-limiting toxicities (DLT) and incidence of adverse events (AE). Secondary endpoints were progression free survival (PFS) and treatment response based on radiographic, intraoperative, and pathological findings. Results: Four patients with LGSOC were enrolled of which three were heavily pretreated. Median prior lines of therapy was 5 (range 2-10). Three patients had extraperitoneal metastases, and two patients had baseline partial small bowel obstructive (SBO) symptoms. Median age of patients was 58 (38-68). PIPAC completion rate (≥2 PIPACs) was 75%. No DLTs or Clavien-Dindo surgical complications occurred. No G4/G5 AEs were observed, and one G3 abdominal pain was reported. One patient had a partial response after 3 cycles of PIPAC and completed an additional 3 cycles with compassionate use amendment. Two patients came off study after 2 cycles due to extraperitoneal progressive disease. One patient came off study after 1 cycle due to toxicity. Median decrease in peritoneal carcinomatosis index between cycles 1 and 2 was 5.0%. Ascites decreased in 2 out of 3 patients who had ≥2 PIPACs. Median PFS was 4.3 months (1.7-21.6), median overall survival was 11.6 months (5.4-30.1), and objective response rate was 25%. Conclusion: PIPAC with cisplatin/doxorubicin is well tolerated in LGSOC patients without baseline SBO symptoms. IP response was seen in 2 out of 3 patients that completed ≥2 PIPAC cycles. Further study of PIPAC for patients with recurrent disease limited to the IP cavity and with no partial SBO symptoms should be considered.

Impact on quality of life, health care access, and health care utilization of individuals with vitiligo: an analysis of the All of Us research program.

Vitiligo is an autoimmune skin depigmenting disorder that can negatively impact quality of life. A new FDA approved treatment for vitiligo offers considerable promise, and to maximize benefits strategies to implementation should consider disease burden, healthcare access, and healthcare utilization of individuals with vitiligo. Using the All of Us Research Program's large data set, including survey responses, we investigated these outcomes among participants with and without vitiligo. Our analysis used quality of life, delayed care due to an obstacle, and seeing a doctor in the past year as dichotomized proxies for disease burden, healthcare access, and healthcare utilization. The results show that people with vitiligo are more likely to report worse quality of life but ostensibly greater healthcare access and utilization compared to people without vitiligo. However, these relationships are not significant when adjusted for demographics, socioeconomic characteristics, and comorbidities of vitiligo. Prior research has shown non-Caucasian individuals have worse health outcomes in general, and worse quality of life within the vitiligo population. Our data demonstrated consistent findings; moreover, we found that non-Caucasian individuals with vitiligo had inferior healthcare access and lower health care utilization than Caucasian individuals. Implementation of new treatments for vitiligo should prioritize disadvantaged individuals to improve health equity.

Health care resource utilization and costs for treatment-experienced people with HIV switching or restarting antiretroviral regimens since 2018.

BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.

Virtual Reality for Subacute Pain After Orthopedic Traumatic Musculoskeletal Injuries: A Mixed Methods Pilot Study.

OBJECTIVES: Acute orthopedic traumatic musculoskeletal injuries are prevalent, costly, and often lead to persistent pain and functional limitations. Psychological risk factors (eg, pain catastrophizing and anxiety) exacerbate these outcomes but are often overlooked in acute orthopedic care. Addressing gaps in current treatment approaches, this mixed-methods pilot study explored the use of a therapeutic virtual reality (VR; RelieVRx ), integrating principles of mindfulness and cognitive-behavioral therapy, for pain self-management at home following orthopedic injury. METHODS: We enrolled 10 adults with acute orthopedic injuries and elevated pain catastrophizing or pain anxiety from Level 1 Trauma Clinics within the Mass General Brigham health care system. Participants completed daily RelieVRx sessions at home for 8 weeks, which included pain education, relaxation, mindfulness, games, and dynamic breathing biofeedback. Primary outcomes were a priori feasibility, appropriateness, acceptability, satisfaction, and safety. Secondary outcomes were pre-post measures of pain, physical function, sleep, depression, and hypothesized mechanisms (pain self-efficacy, mindfulness, and coping). RESULTS: The VR and study procedures met or exceeded all benchmarks. We observed preliminary improvements in pain, physical functioning, sleep, depression, and mechanisms. Qualitative exit interviews confirmed high satisfaction with RelieVRx and yielded recommendations for promoting VR-based trials with orthopedic patients. DISCUSSION: The results support a larger randomized clinical trial of RelieVRx versus a sham placebo control to replicate the findings and explore mechanisms. There is potential for self-guided VR to promote evidence-based pain management strategies and address the critical mental health care gap for patients following acute orthopedic injuries.

Optimizing the Implementation of a Lifestyle Dementia Prevention Intervention for Older Patients in an Academic Healthcare System.

Background: Interventions that promote healthy lifestyles are critical for the prevention of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). However, knowledge of the best practices for implementing AD/ADRD prevention in healthcare settings remains limited. Objective: We aimed to qualitatively identify barriers and facilitators to implementing a clinical trial of a novel lifestyle intervention (My Healthy Brain) in our medical center for older patients with subjective cognitive decline who are at-risk for AD/ADRD. Methods: We conducted focus groups with 26 healthcare professionals (e.g., physicians, psychology, nursing) from 5 clinics that treat older patients (e.g., memory care, psychiatry). Our qualitative analysis integrated two implementation frameworks to systematically capture barriers and facilitators to AD/ADRD prevention (Consolidated Framework for Implementation Science Research) that impact implementation outcomes of acceptability, appropriateness, and feasibility (Proctor's framework). Results: We found widespread support for an RCT of My Healthy Brain and AD/ADRD prevention. Participants identified barriers related to patients (stigma, technological skills), providers (dismissiveness of "worried well," doubting capacity for behavior change), clinics (limited time and resources), and the larger healthcare system (underemphasis on prevention). Implementation strategies guided by Expert Recommendations for Implementing Change (ERIC) included: developing tailored materials, training staff, obtaining buy-in from leadership, addressing stigmatized language and practices, identifying "champions," and integrating with workflows and resources. Conclusions: The results will inform our recruitment, enrollment, and retention procedures to implement the first randomized clinical trial of My Healthy Brain. Our study provides a blueprint for addressing multi-level barriers to the implementation of AD/ADRD prevention for older patients in medical settings.

Effectiveness of the static progressive Joint Active System splint in improving upper extremity joint stiffness.

PURPOSE: Injuries to the upper extremity often result in stiffness. The joint capsule may lose its elastic properties, limiting motion. Most modalities for increasing motion are based on capsule stretching, and usually involve physical or occupational therapy. We tested the hypothesis that the Joint Active System static-progressive splint is helpful in increasing range of motion in stiff joints after failure of other treatments. METHODS: Candidates for the Joint Active System splint were mostly patients with upper extremity trauma that required surgery, if they plateaued after therapy but still had stiffness. A retrospective review was performed of all patients from 2015 to 2019 that met our inclusion criteria. Etiologies of stiffness and patient demographics were documented. Range of motion was recorded before and after treatment and, when available, functional scores were calculated. RESULTS: Forty-four patients were treated with the Joint Active System splint; 5 were excluded, leaving 39 for analysis: 15 elbow, 14 wrist and 10 proximal interphalangeal joints. All patients had received therapy before using the Joint Active System and 11 had tried a dynamic splint in addition to therapy. All joints showed significant improvement in motion after treatment: from 66.5° to 95.7° in the elbow, 63.5° to 81.1° in the wrist and 33.2° to 51.8° in the proximal interphalangeal joint. When functional scores were available before and after treatment, there was significant improvement for both elbow and wrist. Even when the Joint Active System was started many months after injury, it was effective. CONCLUSIONS: Despite reaching a plateau with therapy, the Joint Active System static-progressive splint is effective in improving range of motion in elbow, wrist and finger joints with stiffness following injury or surgery. TYPE OF STUDY: Retrospective case series. LEVEL OF EVIDENCE: Therapeutic, level IV.

Osteosarcopenia and Mortality in Older Adults Undergoing Transcatheter Aortic Valve Replacement.

Importance: Osteosarcopenia is an emerging geriatric syndrome characterized by age-related deterioration in muscle and bone. Despite the established relevance of frailty and sarcopenia among older adults undergoing transcatheter aortic valve replacement (TAVR), osteosarcopenia has yet to be investigated in this setting. Objective: To determine the association between osteosarcopenia and adverse outcomes following TAVR. Design, Setting, and Participants: This is a post hoc analysis of the Frailty in Aortic Valve Replacement (FRAILTY-AVR) prospective multicenter cohort study and McGill extension that enrolled patients aged 70 years or older undergoing TAVR from 2012 through 2022. FRAILTY-AVR was conducted at 14 centers in Canada, the United States, and France between 2012 and 2016, and patients at the McGill University-affiliated center in Montreal, Québec, Canada, were enrolled on an ongoing basis up to 2022. Exposure: Osteosarcopenia as measured on computed tomography (CT) scans prior to TAVR. Main Outcomes and Measures: Clinically indicated CT scans acquired prior to TAVR were analyzed to quantify psoas muscle area (PMA) and vertebral bone density (VBD). Osteosarcopenia was defined as a combination of low PMA and low VBD according to published cutoffs. The primary outcome was 1-year all-cause mortality. Secondary outcomes were 30-day mortality, hospital length of stay, disposition, and worsening disability. Multivariable logistic regression was used to adjust for potential confounders. Results: Of the 605 patients (271 [45%] female) in this study, 437 (72%) were octogenarian; the mean (SD) age was 82.6 (6.2) years. Mean (SD) PMA was 22.1 (4.5) cm2 in men and 15.4 (3.5) cm2 in women. Mean (SD) VBD was 104.8 (35.5) Hounsfield units (HU) in men and 98.8 (34.1) HU in women. Ninety-one patients (15%) met the criteria for osteosarcopenia and had higher rates of frailty, fractures, and malnutrition at baseline. One-year mortality was highest in patients with osteosarcopenia (29 patients [32%]) followed by those with low PMA alone (18 patients [14%]), low VBD alone (16 patients [11%]), and normal bone and muscle status (21 patients [9%]) (P < .001). Osteosarcopenia, but not low VBD or PMA alone, was independently associated with 1-year mortality (odds ratio [OR], 3.18; 95% CI, 1.54-6.57) and 1-year worsening disability (OR, 2.11; 95% CI, 1.19-3.74). The association persisted in sensitivity analyses adjusting for the Essential Frailty Toolset, Clinical Frailty Scale, and geriatric conditions such as malnutrition and disability. Conclusions and Relevance: The findings suggest that osteosarcopenia detected using clinical CT scans could be used to identify frail patients with a 3-fold increase in 1-year mortality following TAVR. This opportunistic method for osteosarcopenia assessment could be used to improve risk prediction, support decision-making, and trigger rehabilitation interventions in older adults.

A unique presentation of the rare Nora's lesion, symptomatic bizarre parosteal osteochondromatous proliferation: A case report.

Bizarre parosteal osteochondromatous proliferations, also known as Nora's lesions, are rare benign tumors with a high recurrence rate. They are often difficult to identify because of their similar appearance to other tumors. We describe a 25-year-old healthy female patient with bizarre parosteal osteochondromatous proliferations in an uncommon location on the pelvic ilium, presenting with unique clinical findings of abdominal pain and femoral paresthesia and showing atypical radiographic findings. To the best of our knowledge, this is one of the very few cases ever reported in the literature of Nora's lesion in this particular location and possibly the first case ever with this specific presentation. The lesions' radiographic images, combined orthopedic and general surgery procedures, and histological analysis are detailed. The patient's continued 4-year follow-up has demonstrated no symptoms or evidence of recurrence.

It Is Time to Reconsider the 3% Discount Rate.

OBJECTIVES: Health technology assessment (HTA) guidance often recommends a 3% real annual discount rate, the appropriateness of which has received limited attention. This article seeks to identify an appropriate rate for high-income countries because it can influence projected cost-effectiveness and hence resource allocation recommendations. METHODS: The author conducted 2 Pubmed.gov searches. The first sought articles on the theory for selecting a rate. The second sought HTA guidance documents. RESULTS: The first search yielded 21 articles describing 2 approaches. The "Ramsey Equation" sums contributions by 4 factors: pure time preference, catastrophic risk, wealth effect, and macroeconomic risk. The first 3 factors increase the discount rate because they indicate future impacts are less important, whereas the last, suggesting greater future need, decreases the discount rate. A fifth factor-project-specific risk-increases the discount rate but does not appear in the Ramsey Equation. Market interest rates represent a second approach for identifying a discount rate because they represent competing investment returns and hence opportunity costs. The second search identified HTA guidelines for 32 high-income countries. Twenty-two provide no explicit rationale for their recommended rates, 8 appeal to market interest rates, 3 to consistency, and 3 to Ramsey Equation factors. CONCLUSIONS: Declining consumption growth and real interest rates imply HTA guidance should reduce recommended discount rates to 1.5 to 2+%. This change will improve projected cost-effectiveness for therapies with long-term benefits and increase the impact of accounting for long-term drug price dynamics, including reduced prices attending loss of market exclusivity.

Racial and ethnic differences in disease course Medicare expenditures for beneficiaries with dementia.

BACKGROUND: Research on racial and ethnic disparities in costs of care during the course of dementia is sparse. We analyzed Medicare expenditures for beneficiaries with dementia to identify when during the course of care costs are the highest and whether they differ by race and ethnicity. METHODS: We analyzed data from the 2000-2016 Health and Retirement Study (HRS) linked with corresponding Medicare claims to estimate total Medicare expenditures for four phases: (1) the year before a dementia diagnosis, (2) the first year following a dementia diagnosis, (3) ongoing care for dementia after the first year, and (4) the last year of life. We estimated each patient's phase-specific and disease course Medicare expenditures by using a race-specific survival model and monthly expenditures adjusted for patient characteristics. We investigated healthcare utilization by service type across races/ethnicities and phases of care. RESULTS: Adjusted mean total Medicare expenditures for non-Hispanic (NH) Black ($165,730) and Hispanic beneficiaries with dementia ($160,442) exceeded corresponding expenditures for NH Whites ($136,326). In the year preceding and immediately following initial dementia diagnosis, mean Medicare expenditures for NH Blacks ($26,337 and $20,429) exceeded expenditures for Hispanics and NH Whites ($21,399-23,176 and 17,182-18,244). The last year of life was responsible for the greatest cost contribution: $51,294 (NH Blacks), $47,469 (Hispanics), and $39,499 (NH Whites). These differences were driven by greater use of high-cost services (e.g., emergency department, inpatient and intensive care), especially during the last year of life. CONCLUSIONS: NH Black and Hispanic beneficiaries with dementia had higher disease course Medicare expenditures than NH Whites. Expenditures were highest for NH Black beneficiaries in every phase of care. Further research should address mechanisms of such disparities and identify methods to improve communication, shared decision-making, and access to appropriate services for all populations.

Amygdala-hippocampus somatostatin interneuron beta-synchrony underlies a cross-species biomarker of emotional state.

Emotional responses arise from limbic circuits including the hippocampus and amygdala. In the human brain, beta-frequency communication between these structures correlates with self-reported mood and anxiety. However, both the mechanism and significance of this biomarker as a readout vs. driver of emotional state remain unknown. Here, we show that beta-frequency communication between ventral hippocampus and basolateral amygdala also predicts anxiety-related behavior in mice, both on long timescales (∼30 min) and immediately preceding behavioral choices. Genetically encoded voltage indicators reveal that this biomarker reflects synchronization between somatostatin interneurons across both structures. Indeed, synchrony between these neurons dynamically predicts approach-avoidance decisions, and optogenetically shifting the phase of synchronization by just 25 ms is sufficient to bidirectionally modulate anxiety-related behaviors. Thus, back-translation establishes a human biomarker as a causal determinant (not just predictor) of emotional state, revealing a novel mechanism whereby interregional synchronization that is frequency, phase, and cell type specific controls emotional processing.

Machine learning to detect the SINEs of cancer.

We previously described an approach called RealSeqS to evaluate aneuploidy in plasma cell-free DNA through the amplification of ~350,000 repeated elements with a single primer. We hypothesized that an unbiased evaluation of the large amount of sequencing data obtained with RealSeqS might reveal other differences between plasma samples from patients with and without cancer. This hypothesis was tested through the development of a machine learning approach called Alu Profile Learning Using Sequencing (A-PLUS) and its application to 7615 samples from 5178 individuals, 2073 with solid cancer and the remainder without cancer. Samples from patients with cancer and controls were prespecified into four cohorts used for model training, analyte integration, and threshold determination, validation, and reproducibility. A-PLUS alone provided a sensitivity of 40.5% across 11 different cancer types in the validation cohort, at a specificity of 98.5%. Combining A-PLUS with aneuploidy and eight common protein biomarkers detected 51% of the cancers at 98.9% specificity. We found that part of the power of A-PLUS could be ascribed to a single feature-the global reduction of AluS subfamily elements in the circulating DNA of patients with solid cancer. We confirmed this reduction through the analysis of another independent dataset obtained with a different approach (whole-genome sequencing). The evaluation of Alu elements may therefore have the potential to enhance the performance of several methods designed for the earlier detection of cancer.

Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape.

Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD. This screen implicated disruption of kinase SMG1's phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from truncating mutations in vivo and in vitro . Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable HLA class I-associated peptides from NMD-downregulated proteins on the surface of cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases. One Sentence Summary: Disruption of the nonsense-mediated decay pathway with a newly developed SMG1 inhibitor with in-vivo activity increases the expression of T-cell targetable cancer neoantigens resulting from truncating mutations.

Ofranergene Obadenovec (Ofra-Vec, VB-111) With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer: Randomized Controlled Phase III Trial (OVAL Study/GOG 3018).

PURPOSE: To evaluate the addition of ofranergene obadenovec (ofra-vec, VB-111), a novel gene-based anticancer targeted therapy, to once a week paclitaxel in patients with recurrent platinum-resistant ovarian cancer (PROC). METHODS: This placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT03398655) randomly assigned patients with PROC 1:1 to receive intravenous ofra-vec every 8 weeks with once a week IV paclitaxel or placebo with paclitaxel until disease progression. The dual primary end points were overall survival (OS) and progression-free survival (PFS) as assessed by Blinded Independent Central Review. RESULTS: Between December 2017 and March 2022, 409 patients were randomly assigned. The median PFS was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, hazard ratio (HR) 1.03 (CI, 0.83 to 1.29; P = .7823). The median OS with ofra-vec was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27; P = .8440). Objective response rates (ORRs) per RECIST 1.1 were similar in both arms: 28.9% with ofra-vec versus 29.6% with control. In both treatment arms, response to CA-125 was a substantial prognostic factor for both PFS and OS. In the ofra-vec arm, the HR in CA-125 responders compared with that in nonresponders for PFS was 0.2428 (CI, 0.1642 to 0.3588), and for OS, the HR was 0.3343 (CI, 0.2134 to 0.5238). Safety profile was characterized by common transient flu-like symptoms such as fever and chills. CONCLUSION: The addition of ofra-vec to paclitaxel did not improve PFS or OS. The PFS and ORR in the control arm exceeded the results that were anticipated on the basis of the AURELIA chemotherapy control arm. CA-125 response was a substantial prognostic biomarker for PFS and OS in patients with PROC treated with paclitaxel.

Update on guidelines and recommendations for enhanced recovery after thoracic surgery.

PURPOSE OF REVIEW: Enhanced recovery after thoracic surgery (ERATS) has continued its growth in popularity over the past few years, and evidence for its utility is catching up to other specialties. This review will present and examine some of that accumulated evidence since guidelines sponsored by the Enhanced Recovery after Surgery (ERAS) Society and the European Society of Thoracic Surgeons (ESTS) were first published in 2019. RECENT FINDINGS: The ERAS/ESTS guidelines published in 2019 have not been updated, but new studies have been done and new data has been published regarding some of the individual components of the guidelines as they relate to thoracic and lung resection surgery. While there is still not a consensus on many of these issues, the volume of available evidence is becoming more robust, some of which will be incorporated into this review. SUMMARY: The continued accumulation of data and evidence for the benefits of enhanced recovery techniques in thoracic and lung resection surgery will provide the thoracic anesthesiologist with guidance on how to best care for these patients before, during, and after surgery. The data from these studies will also help to elucidate which components of ERAS protocols are the most beneficial, and which components perhaps do not provide as much benefit as previously thought.

Closed-loop neurostimulation for the treatment of psychiatric disorders.

Despite increasing prevalence and huge personal and societal burden, psychiatric diseases still lack treatments which can control symptoms for a large fraction of patients. Increasing insight into the neurobiology underlying these diseases has demonstrated wide-ranging aberrant activity and functioning in multiple brain circuits and networks. Together with varied presentation and symptoms, this makes one-size-fits-all treatment a challenge. There has been a resurgence of interest in the use of neurostimulation as a treatment for psychiatric diseases. Initial studies using continuous open-loop stimulation, in which clinicians adjusted stimulation parameters during patient visits, showed promise but also mixed results. Given the periodic nature and fluctuations of symptoms often observed in psychiatric illnesses, the use of device-driven closed-loop stimulation may provide more effective therapy. The use of a biomarker, which is correlated with specific symptoms, to deliver stimulation only during symptomatic periods allows for the personalized therapy needed for such heterogeneous disorders. Here, we provide the reader with background motivating the use of closed-loop neurostimulation for the treatment of psychiatric disorders. We review foundational studies of open- and closed-loop neurostimulation for neuropsychiatric indications, focusing on deep brain stimulation, and discuss key considerations when designing and implementing closed-loop neurostimulation.

POLD1 DEDD Motif Mutation Confers Hypermutation in Endometrial Cancer and Durable Response to Pembrolizumab.

BACKGROUND: Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic. METHODS: A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient's tumor and engineered cell lines. RESULTS: Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A POLD1-specific mutational signature was found in both the patient's tumor and POLD1(p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI). CONCLUSION: Charge-discordant AA substitution in the DEDD motif of POLD1 is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.